Inflammatory arthritis is a musculoskeletal disorder and the leading cause of disability in the United States. Forty million Americans, representing 15% of the population, have some form of arthritis, and that figure is expected to increase to 59.4 million (18.2%) by the year 2020, an increase of 57% in the number of persons affected. Arthritis patients make more than 315 million physician visits and are hospitalized more than 8 million times a year. Arthritis costs the nation more than $65 billion annually in medical costs and lost productivity. Osteoarthritis (OA), or degenerative joint disease, is the most common type of arthritis, affecting 20.7 million people, (12.1%) of U.S. adults in 1990, now estimated at 37 million, and trailed chronic heart disease as the leading cause of Social Security payments due to long-term absence from work. (Lawrence, Helmick et al. 1998).
Approximately 1-2% of the population suffers from rheumatoid arthritis (RA), which is characterized as an imbalance in the immune system that causes an overproduction of pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNF-α, interleukin 1 (IL-1), and a lack of anti-inflammatory cytokines, e.g. IL-10, IL-11. RA is characterized by synovial inflammation, which progresses to cartilage destruction, bone erosion and subsequent joint deformity. The primary symptoms of RA are joint inflammation, swelling, difficulty moving, and pain. During the inflammatory process, polymorphonuclear cells, macrophages, and lymphocytes are released. Activated T-lymphocytes produce cytotoxins and pro-inflammatory cytokines, while macrophages stimulate the release of prostaglandins and cytotoxins. Vasoactive substances (histamine, kinins, and prostaglandins) are released at the site of inflammation and cause edema, warmth, erythema, and pain associated with inflamed joints. In the late stage of RA, enzymes produced by the inflamed cells may digest bone and cartilage. The long-term damage results in chronic pain, loss of function, deformity, disability in the joints and even a shortened life expectancy. The prevalence of RA around world is constantly at 0.5-1.0% of total population, with exceptions in the Pima Indians and the Chippewa Indians at higher rates of 5.3% and 6.8%, respectively, and in Chinese and Japanese reportedly at lower rates (Silman and Pearson 2002).
Osteoarthritis usually presents as pain, which worsens with exercise or simply an X-ray that clearly shows thinning cartilage. Common joints affected are the knees, hips and spine, finger, base of thumb and base of the big toe. Osteoarthritis is characterized by degenerative changes in the articular cartilage and subsequent new bone formation at the articular margins. The primary defect in hyaline cartilage, at the articular surface of the joint, is an alteration in the ratio of total glycosaminoglyeans to that of the collagen fiber content in the matrix. By age 60, almost all Americans have osteoarthritis in their necks or spines.
Current medications to treat inflammatory arthritis can be classified as analgesics; corticosteroids (e.g., glucocorticoids, or steroids); NSAIDs (non-steroidal anti-inflammatory drugs); DMARDS (disease-modifying anti-rheumatic drugs), and biologic DMARDS.
Controlling pain is a vital part of treating arthritis. Analgesics can only provide a temporary pain relief. They neither reduce inflammation nor slow progression of the disease. Acetaminophen (Tylenol) is the most commonly used analgesic. Narcotic analgesic drugs can also be prescribed for more severe pain.
Corticosteroids are closely related to cortisol, a hormone produced on the cortex of the adrenal glands. Treatment of rheumatoid arthritis with corticosteroids remains controversial in terms of benefit/harm trade-offs (Boers 2004). Corticosteroids are considered as very potent drugs because of their ability to reduce swelling and inflammation rapidly. However, it is well known that corticosteroids can potentially cause serious and permanent side effects. Therefore, they may only be used in certain situations systemically or locally into a specific joint for relief, always at the lowest possible effective dose for the shortest possible duration with gradually weaning off or tapering the dose over time.
NSAIDs are distinguished from coticosteroids. NSAIDs at low doses reduce pain, and at higher doses relieve inflammation. Most NSAIDs are inhibitors of the enzyme cyclooxygenase, inhibiting non-selectively both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Cyclooxygenase is the rate-limiting enzyme in catalyzing the formation of prostaglan prostaglandins and thromboxane from arachidonic acid. Prostaglandins among others function as messenger molecules in the process of inflammation. COX-1 is an enzyme constitutively expressed with a “house-keeping” role in regulating many normal physiological processes. The adverse effects of NSAIDs are mainly related to their inhibition of COX-1 in kidney and gastrointestinal tracts where prostaglandins serve a protective role. COX-2 is an enzyme with low or non-detectable expression in most tissues, but can be readily induced in response to cell activation by cytokines, growth factors and tumor promoters. Therapeutic effects of NSAIDs are due to their inhibition on COX-2. While selective COX-2 inhibitors, Coxibs (celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib), were thought to have anti-inflammatory action without disrupting gastroprotective prostaglandins, an increased cardiovascular risk was seen in clinical applications which resulted in the worldwide withdrawal of some Coxibs (rofecoxib and Valdecoxib) (Caporali and Montecucco 2005).
While the NSAID reduces day-to-day inflammation, stronger medicines, DMARDs, are usually required for patients with persistent inflammation in several joints due to inflammatory arthritis for longer than six weeks. The DMARDs slow down the biological processes that are the driving force behind persistent inflammation. DMARDs are slow-acting anti-rheumatic drugs. The quickest-acting DMARD is methotrexate, which usually takes four to six weeks before seeing benefits. The rest of the DMARDs can take three to six months or even longer to be effective. As DMARDs suppress the immune system, serious adverse effects may occur over long-term use. Methotrexate has emerged as an effective treatment for RA either as a single agent or in combination with other DMARDs (Borchers, Keen et al. 2004). The toxicity profile of methotrexate is well established and includes serious and sometimes fatal liver disease, pneumonitis, and cytopenias.
The most exciting progress in recent years in the treatment of RA is the development of biologic DMARDs (Klippel 2000). Elucidation of the key role of TNF-α in the pathogenesis of RA has led to the development of targeted therapeutics blocking the activity of this cytokine. In addition to anti-TNF therapy, a number of other biologic DMARDs have been developed specifically against molecules (IL-1) or cells (B cells and T cells) involved in the process of immune-related diseases. Potential advantages of biologic DMARDs over traditional DMARDs, include highly specific blockage of the target molecules critically involved in the pathogenesis, rapid onset of clinical action, minimized nonspecific toxicity, long dosing intervals (every other week subcutaneously or every other month intravenously), possible long-term immunomodulatory effects, and improved quality of life. Biological DMARDs used for arthritis include those blocking inflammatory cytokines (Maini and Taylor 2000), specifically depleting B cells (Higashida, Wun et al. 2005) and selectively inhibiting activation of T cells (Kremer et al, 2005).
Since biological DMARDs have only recently been in clinical use, their long term efficacy and adverse effects remain to be evaluated. In theory, strong and specific blockage or depletion of molecules or cells that are critically involved in normal physiological process will inevitably result in undesirable consequence (Mencher and Wang 2005). In deed, serious infections and tumors have been observed in trials with small cohorts of patients taking anti-TNF therapy (Askling, Fored et al. 2005; Chakravarty, Michaud et al. 2005; Listing, Strangfeld et al. 2005). A collective of randomized, placebo-controlled trials of the anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis indicates that anti-TNF-treated patients (3493 patients) compared with placebo patients (1512 patients) have significant increase in incidence of serious infections (relative risk: 2.0) and malignancies (relative risk: 3.3)(Bongartz, Sutton et al. 2006).
All these biological DMARDs are either recombinant proteins or antibodies. They are very expensive. Yearly cost for a patient typically exceeds $12,000. The cost of biological DMARDs administrated by injection or perfusion is the major drawback limiting greater use (Wong 2004).
Although a wide range of drugs are available, the successful and cost effective treatment of inflammatory arthritis is still a major unmet medical need. While biologic DMARDs are offering the most promising route to slowing or even halting this disease, they are expensive and work only for a proportion of patients. Even for the most effective anti-TNF therapy, at least one third of RA patients do not respond (Navarro-Sarabia, Ariza-Ariza et al. 2006; Symmons and Silman 2006; Moreland 2005; and Reimold 2002).